PROJECT SUMMARY/ABSTRACT Mild traumatic brain injury (MTBI) has been called the signature injury of the wars in Iraq (operation Iraqi freedom; OIF) and Afghanistan (operation enduring freedom; OEF). In both theatres of operation, TBI has been a significant cause of mortality and morbidity with blast related injury the most common cause. Animal studies clearly show that blast overpressure (BOP) waves are transmitted to brain. One striking feature of the MTBI cases being seen in veterans of the wars in Iraq and Afghanistan is the high association of MTBI with post-traumatic stress disorder (PTSD). Indeed the high prevalence of PTSD and depression in returning OIF/OEF veterans with MTBI is now well documented and the distinction between the two disorders has proven a clinically challenging exercise. The high prevalence of PTSD in OIF/OEF veterans with MTBI might be explained by co-incident exposures to both TBI events as well as PTSD stressors. However, an alternative hypothesis is that blast related MTBI damages brain structures that are important in mediating responses to psychological stressors and thus enhances the likelihood of developing PTSD when exposed to subsequent stressors. Here using a rat model of blast induced MTBI developed by our collaborator on this project, Dr. Stephen Ahlers CAPT(r) a Department of Defense funded investigator at the Naval Medical Research Center in Silver Spring MD, we will explore this hypothesis through four specific aims. We will perform a detailed behavioral characterization of rats exposed to single or repeated BOP injury with an emphasis on behavioral and cognitive traits related to the cognitive and behavioral changes associated with human PTSD and TBI (aim #1) and determine whether BOP exposure predisposes to the development of PTSD like traits following exposure to a PTSD stressor (a predator scent) using a well-established rat model (aim #2). We will in addition determine the structural effects of acute or repeated BOP exposure on the prefrontal cortex, amygdala and hippocampus, the principal anatomic substrates that are thought to underlie the neurobiological basis of PTSD (aim #3) and examine whether hippocampal neurogenesis may be altered following BOP exposure (aim #4). Collectively these studies will contribute to a better understanding of the neurobiological effects of blast related MTBI and whether blast related brain injury itself may contribute to the high prevalence of PTSD seen in this patient population.